Enolate Conjugate Addition to Alkylidene Bis-Sulfoxides: Sphaeric Acid Synthesis and Absolute Configuration Determination

Abstract

The first stereoselective synthesis of sphaeric acid is described. The key step of this synthesis is an efficient ester enolate conjugate addition onto alkylidene bis-sulfoxides with good to high diastereoselectivity. Formation of sphaeric acid allowed the determination of its absolute configuration as 2R,3R.

alkylidene bis-sulfoxides - sphaeric acid - enolate addition - succinic acid - E/Z-enolate

References and Notes

<A NAME="RG40005ST-1A">1a</A>

The more accurate name is ‘alkenylidene bis-sulfoxides’ but ‘alkylidene bis-sulfoxides’ is conveniently used in analogy with the corresponding malonate derivatives.

<A NAME="RG40005ST-1B">1b</A> For a review on bis-sulfoxides, see: Delouvrié B. Fensterbank L. Nájera F. Malacria M. Eur. J. Org. Chem.  2002,  3507 

<A NAME="RG40005ST-2A">2a</A> Aggarwal VK. Roseblade SJ. Barrell JK. Alexander R. Org. Lett.  2002,  4:  1227 

<A NAME="RG40005ST-2B">2b</A> Aggarwal VK. Steele RM. Barrell JK. Grayson I. J. Org. Chem.  2003,  68:  4087 

<A NAME="RG40005ST-2C">2c</A> Aggarwal VK. Barrell JK. Worrall JM. Alexander R. J. Org. Chem.  1998,  63:  7128 

<A NAME="RG40005ST-3">3</A> Brebion F. Delouvrié B. Nájera F. Fensterbank L. Malacria M. Vaissermann J. Angew. Chem. Int. Ed.  2003,  42:  5342 

<A NAME="RG40005ST-4">4</A> Brebion F. Goddard J.-P. Fensterbank L. Malacria M. Synthesis  2005,  2449 

<A NAME="RG40005ST-5">5</A> Wedel T. Podlech J. Org. Lett.  2005,  7:  4013 

<A NAME="RG40005ST-6">6</A> Delouvrié B. Nàjera F. Fensterbank L. Malacria M. J. Organomet. Chem.  2002,  643-644:  130 

<A NAME="RG40005ST-7A">7a</A> Heathcock CH. Young SD. Hagen JP. Pirrung MC. White CT. VanDerveer D. J. Org. Chem.  1980,  45:  3846 

<A NAME="RG40005ST-7B">7b</A> Heathcock CH. Pirrung MC. Young SD. Hagen JP. Jarvi ET. Badertscher U. Märki H.-P. Montgomery SH. J. Am. Chem. Soc.  1984,  106:  8161 

<A NAME="RG40005ST-7C">7c</A> Heathcock CH. Oare DA. J. Org. Chem.  1985,  50:  3022 

<A NAME="RG40005ST-7D">7d</A> Heathcock CH. Oare DA. J. Org. Chem.  1990,  55:  157 

<A NAME="RG40005ST-8">8</A>

Enolate Conjugate AdditionGeneral Procedure A ( E -Enolate): To a solution of LDA (2 equiv) in THF (2.4 mL/mmol) at -78 °C, a solution of ester (2 equiv) in THF (1.4 mL/mmol) was added. After
45 min at -78 °C, a solution of alkylidene bis-sulfoxide (1 equiv) in THF (4.8 mL) was added via cannula. The reaction mixture was stirred at -78 °C for 15 min, quenched with an aq sat. solution of NH₄Cl, and diluted with CH₂Cl₂. The organic layer was washed with water, brine, dried over MgSO₄, and concentrated in vacuo. The residue was purified by silica gel chromatography.
Procedure B ( Z -Enolate): To a solution of LDA (2 equiv) in THF (2.4 mL/mmol) at -78 °C, freshly distilled HMPA (8 equiv) and a solution of ester (2 equiv) in THF (1.4 mL/mmol) was added. After 45 min at -78 °C, a solution of alkylidene bis-sulfoxide (1 equiv) in THF (4.8 mL) was added via cannula. The reaction mixture was stirred at
-78 °C for 15 min, quenched with an aq sat. solution of NH₄Cl and diluted with CH₂Cl₂.The organic layer was washed with water, brine, dried over MgSO₄, and concentrated in vacuo. The residue was purified by silica gel chromatography. ( S _S , S _S ,3 R )-3-[Bis( p -tolylsulfinyl)methyl]undecanoic Acid tert -Butyl Ester ( 7): Prepared by general procedure A from 1 (50 mg, 0.12 mmol). Column chromatography (pentane-EtOAc, 90:10 to 80:20) afforded 52 mg (81%) of 6 as a colorless oil; [α]_D ²⁰ +79.0 (c 0.4, CHCl₃). IR (neat): 2926, 2855, 1728, 1492, 1367, 1152, 1086, 1058, 811, 755 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.85 (t, J = 7.0 Hz, 3 H, CH₂CH ₃), 0.90-1.27 (m, 14 H, 7 × CH₂), 1.42 [s, 9 H, C(CH₃)₃], 2.31 (s, 3 H, p-Tol), 2.44 (s, 3 H, p-Tol), 2.69 [dd, J = 16.6, 8.6 Hz, 1 H, CHHCO₂C(CH₃)₃], 2.82 [m, 1 H, CHCH(SOp-Tol)₂], 3.18 [dd, J = 16.6, 3.3 Hz, 1 H, CHHCO₂C(CH₃)₃], 3.60 [d, J = 4.4 Hz, 1 H, CH(SOp-Tol)₂], 6.88 (d, J = 8.2 Hz, 2 H, Ar), 7.12 (d, J = 8.0 Hz, 2 H, Ar), 7.37 (d, J = 8.0 Hz, 2 H, Ar), 7.54 (d, J = 8.2 Hz, 2 H, Ar). ¹³C NMR (100 MHz, CDCl₃): δ = 14.4 (CH₂ CH₃), 21.5 (p-Tol), 21.8 (p-Tol), 22.9, 26.7, 29.2, 29.3, 29.6, 32.1, 32.6 (7 × CH₂), 28.4 [C(CH₃)₃], 31.5 [CHCH(SOp-Tol)₂], 37.3 [CH₂CO₂C(CH₃)₃], 80.8 [CO₂ C(CH₃)₃], 89.2 [CH(SOp-Tol)₂], 124.0 (2 C, ArCH), 125.0 (2 C, ArCH), 130.1 (2 C, ArCH), 130.4 (2 C, ArCH), 139.2, 140.9, 141.2, 142.3 (4 C, ArCH), 171.8 (CO). HRMS: m/z calcd for C₃₀H₄₄O₄NaS₂ [M + Na]⁺: 555.2579; found: 555.2584.

<A NAME="RG40005ST-9">9</A> Heathcock CH. Pirrung MC. Montgomery J. Lampe J. Tetrahedron  1981,  37:  4087 

<A NAME="RG40005ST-10">10</A> Bürgi HB. Dunitz JD. Acc. Chem. Res.  1983,  16:  153 

<A NAME="RG40005ST-11">11</A> Wilkinson RA. Strobel G. Stierle A. J. Nat. Prod.  1999,  62:  358 

<A NAME="RG40005ST-12">12</A>

epi -Sphaeric Acid ( 14): White solid; mp 121-125 °C (dec.); [α]_D ²⁰ +18.9 (c 1.1, CH₃OH). IR (neat): 3100, 2918, 2852, 2615, 1689, 1462, 1419, 1275, 1198, 945 cm^-1. ¹H NMR (400 MHz, CD₃OD): δ = 0.93 (t, J = 7.1 Hz, 3 H, CH₂CH ₃), 1.19 (d, J = 6.6 Hz, 3 H, CH ₃CH), 1.32 (br s, 12 H, 6 × CH₂), 1.51 (m, 1 H, CH₂), 1.63 (m, 1 H, CH₂), 2.54-2.62 (m, 2 H, 2 × CHCOOH). ¹³C NMR (100 MHz, CD₃OD): δ = 15.3 (CH₃), 16.9 (CH₃CH), 24.6, 29.3, 31.2, 31.3 (2 C), 32.9, 33.9 (7 × CH₂), 44.4, 51.0 (2 × CHCOOH), 178.9, 179.5 (2 × COOH). HRMS: m/z calcd for C₁₃H₂₄NaO₄ [M + Na]⁺: 267.1572; found: 267.1602.

<A NAME="RG40005ST-13">13</A> Zhang Q. Remsen EE. Wooley KL. J. Am. Chem. Soc.  2000,  122:  3642 

<A NAME="RG40005ST-14">14</A>

Sphaeric Acid ( 16): Colorless oil; [α]_D ²⁰ +8.1 (c 0.78, MeOH). IR (neat): 3027, 3018, 2924, 2855, 2680, 1705, 1464, 1416, 1282, 1240, 932 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.90 (t, J = 6.6 Hz, 3 H, CH₂CH ₃), 1.27-1.36 (m, 15 H, 6 × CH₂, CH₂CH ₃), 1.56-1.63 (m, 2 H, CH₂), 2.57 (dt, 1 H, J = 9.6, 4.3 Hz, CH), 2.72 (dq, J = 9.8, 4.2 Hz, 1 H, CH), 11.04 (br s, 2 H, CO₂H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.1 (CH₃), 15.2 (CH₃), 22.7, 26.5, 29.2 (2 C), 29.3, 29.5, 31.8 (7 × CH₂), 40.9, 47.9 (2 CHCOOH), 181.9, 182.5 (2 × COOH).